Our laboratory investigations are focused on identifying genes that regulate growth, differentiation, and programmed cell death of normal and malignant mammary epithelial cells in order to develop rational strategies for the treatment of breast cancer. We have two ongoing projects: (1) The Epidermal Growth Factor Receptor (EGFR) family (which includes the EGFR, erb-B2, erb-B3, and erb-B4) are a family of growth factor receptors which are frequently amplified and mutated in epithelial malignancies including breast cancer. Understanding the mechanisms that regulate signaling by these receptors should uncover new ways to inhibit cancer cell growth. We have cloned cbl-b and cbl-3, two new mammalian proteins with homology to the c-cbl proto-oncogene. Studies in the nematode C. elegans suggest that the cbl proteins are suppressors of epidermal growth factor receptor (EGFR) signaling. Our work, along with that of others, has shown that cbl proteins inhibit EGFR signaling by enhancing ubiquitination and degradation of the activated receptors. Ongoing work is focused on further elucidating the mechanisms of cbl protein function and to elucidate the differences between the three mammalian cbl proteins. (2) We are investigating the expression and function of death receptors of the TNFR family (e.g. TNFR, Fas, Dr3, Dr4, and Dr5) and their ligands (e.g. TNF, Fas Ligand, and TRAIL) in normal and malignant breast epithelial cells. We have recently shown that most breast cancer cell lines are resistant to the induction of apoptosis by the TRAIL ligand and that this resistance can be overcome by co-incubation of the cells with sub-toxic doses of drugs such as adriamycin. Our current work is focused on understanding the mechanisms that underlie the cancer cells' resistance to death mediated by these receptors, on elucidating the mechanism of the synergy between chemotherapuetic drugs and these death receptors, and on modulating these pathways in breast cancer cells in vitro and in vivo.